Abstract
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options. Although single-cell and spatial transcriptomics have revealed cellular heterogeneity within the IPF lung microenvironment, the immune drivers with causal relevance remain poorly defined. Here, through large-scale Mendelian randomization integrating multi-omics data, we identified a consistent negative causal association between the proportion of CD4⁺ effector memory T cells re-expressing CD45RA (TEMRA) and IPF risk. Multi-platform validation—including single-cell RNA sequencing, flow cytometry, and multiplex immunofluorescence—confirmed a significant reduction in CD4⁺ TEMRA frequency in both peripheral blood and lung tissues of IPF patients, establishing this subset as a clinically relevant biomarker. Spatial transcriptomics further revealed a negative correlation between TEMRA differentiation signatures and local fibrotic burden. Mechanistically, integrated single-cell analyses pinpointed metaplastic KRT5⁺ basal cells as a key epithelial population with the capacity to disrupt immune homeostasis. These aberrant epithelial cells upregulate Galectin-7 (
LGALS7
), which we demonstrate competes with IL-7 for receptor binding, suppresses
STAT5
phosphorylation, and limits CD4⁺ TEMRA differentiation, thereby uncovering a previously unrecognized epithelial–immune crosstalk axis in IPF. Guided by these findings, virtual screening of 20,000 compounds identified neoeriocitrin as a Galectin-7 inhibitor that restores
STAT5
phosphorylation in vitro and attenuates pulmonary fibrosis in vivo. This study positions Galectin-7 as a druggable target and establishes a novel framework linking epithelial dysfunction to immune dysregulation in IPF.